Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota

Dietary methionine restriction has been reported to protect from cancer. Ji et al. describe a cancer-promoting effect of methionine restriction mediated by gut microbiota-induced sulfur deficiency and suppression of antitumour immunity. Restriction of methionine (MR), a sulfur-containing essential amino acid, has been reported to repress cancer growth and improve therapeutic responses in several preclinical settings. However, how MR impacts cancer progression in the context of the intact immune system is unknown. Here we report that while inhibiting cancer growth in immunocompromised mice, MR reduces T cell abundance, exacerbates tumour growth and impairs tumour response to immunotherapy in immunocompetent male and female mice. Mechanistically, MR reduces microbial production of hydrogen sulfide, which is critical for immune cell survival/activation. Dietary supplementation of a hydrogen sulfide donor or a precursor, or methionine, stimulates antitumour immunity and suppresses tumour progression. Our findings reveal an unexpected negative interaction between MR, sulfur deficiency and antitumour immunity and further uncover a vital role of gut microbiota in mediating this interaction. Our study suggests that any possible anticancer benefits of MR require careful consideration of both the microbiota and the immune system.

Automated summary

Dietary methionine restriction can protect against cancer, but this study found that it can promote cancer through gut microbiota-induced sulfur deficiency and suppression of antitumour immunity. It was observed that methionine restriction inhibits cancer growth in immunocompromised mice but reduces T cell abundance, exacerbates tumour growth, and impairs tumour response to immunotherapy in immunocompetent mice. The study reveals the important role of gut microbiota in mediating the negative interaction between methionine restriction, sulfur deficiency, and antitumour immunity.